P369: A PHASE II STUDY OF MINI-HYPER-CVD PLUS VENETOCLAX IN PATIENTS WITH PHILADELPHIA CHROMOSOME-NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: J. Senapati, H. Kantarjian, N. Short, M. Konopleva, F. Ravandi, N. Jain, P. A. Thompson, N. Pemmaraju, W. G. Wierda, G. Borthakur, T. M. Kadia, G. Garcia-Manero, M. Yilmaz, J. Thankachan, M. Zhao, C. Loiselle, M. T. Talley, M. I. Kwari, R. S. Garris, E. J. Jabbour
Journal: HemaSphere (2022)

Background: Venetoclax (VEN), an orally active Bcl-2 antagonist, has shown activity in acute lymphoblastic leukemia (ALL) in preclinical models and in combination with navitoclax (BCL-XL inhibitor) in early clinical studies. Combining VEN with other active agents in ALL might synergize this antileukemic effect. Aims: We aimed to evaluate the efficacy and tolerability of VEN added to mini-hyper CVD (mHCVD) chemotherapy in patients (pts) with relapsed/refractory (R/R) ALL. Methods: Pts ≥18 years of age with R/R Philadelphia chromosome negative (Ph-) B- or T-cell ALL/lymphoblastic lymphoma (LBL) were eligible. Pts were required to have a PS of ≤3, bilirubin ≤1.5 mg/dl, AST/ALT ≤3 x ULN and creatinine ≤2 mg/dl. Treatment consisted of mHCVD for up to 8 cycles. VEN was given at a dose of 400 mg daily on D1-14 of C1 and on D1-7 of C2-8. Rituximab (if CD20+) and prophylactic IT chemotherapy x 8 doses were given in C1-C4. Pts with T-cell ALL received an additional 2 cycles of nelarabine (650 mg/m2 daily on D1-5) and peg-asparaginase (1,500 IU/m2 [capped at 3750 IU] on D5), without VEN, during consolidation and another 2 cycles during maintenance. Responding pts received vincristine and prednisone maintenance with VEN daily on D1-14 of each 28-day cycle for up to 2 yrs. Results: From 6/2019 to 2/2021, 20 pts with R/R ALL were treated, 15 (75%) with B-ALL, 4 (20%) with T-ALL (including 1 ETP-ALL) and 1 (5%) with T-LBL. The median age was 45 yrs (range, 20-70). The median lines of prior therapy was 2 (range 1-5). Of the 15 B-ALL pts, 6 had previously received both blinatumomab (blina) and inotuzumab (INO), 7 had received blina without INO, and 2 had received neither. Overall, 11 pts (55%) had undergone prior stem cell transplantation (SCT). Pt disposition is shown in Fig. 1A. One pt was in measurable residual disease (MRD)-positive CR at trial enrollment; all others had active disease and were evaluable for response assessment. Pts received a median of 2 cycles of mHCVD-VEN (range, 1-6). Overall, 12 of 19 evaluable pts (63%) responded (9 CR, 3 CRi), 9 (75%) of whom after 1 cycle. Response in B-ALL was 9/15 (60%) and in T-ALL was 3/4 (75%). Six of the 12 responders (50%) attained MRD negativity (MRD-ve). Of the 12 responders, 4 (33%) underwent SCT, 3 of whom subsequently relapsed and 1 of whom is in continued MRD-ve CR. All of the 8 responders (67%) who did not undergo SCT, subsequently relapsed and died, with a median duration of response of 2.1 mos. Six of the 7 non-responders have died. With a median follow up of 15 months (mos), 5 pts are alive with a median RFS and OS of 6.2 and 7.1 mos respectively (Fig. 1B. The median OS in responders was 8.8 mos (Fig. 1C). Fig.1: (A) Patient disposition and survival, (B) OS and RFS for the entire cohort, (C) OS of responders and non-responders The therapy was generally well-tolerated. There were no grade 4-5 adverse events. Four pts had a grade 3 related event (hyperbilirubinemia and mucositis in 1 pt and transaminitis, fatigue and tumor lysis syndrome in 1 pt each). One pt required VEN dose reduction due to cytopenias. The median times to neutrophil and platelet recovery in C1 in responding pts were 18 and 27 days, respectively. Image:Summary/Conclusion: Low dose combination chemotherapy with VEN in a population of heavily pretreated R/R ALL was well-tolerated and resulted in a response rate of 63%. This study has now been amended to add navitoclax in an attempt to further improve outcomes.